A state of the art metabolomics core will be a vital part of the Undiagnosed Diseases Network (UDN). However, in order for the UDN to realize it's the full potential it is essential that the metabolomics core doesn't simply function as a high tec referral lab. We propose the formation of a partnership that will combine the state of the art analytical capabilities of the Pacific Northwest National Laboratory (PNNL), with clinical, genetic and bioinformatics expertise from Oregon Health & Science University (OHSU), to create a metabolomics core that functions as a fully integrated component of the network. The integration of this combined expertise will facilitate the linkage of novel metabolites or patterns of metabolites identified by the metabolomics core to the underlying metabolic and genetic derangements, as well as clinical signs and symptoms, and to translate this knowledge into specific clues regarding the genetic etiology of the patient's disorder. The major goal of this metabolomics core is to provide metabolomics assays and computational resources that will address the enormous challenges in developing a modern approach to the use of metabolomics in the diagnosis of disease. To achieve these objectives, we will interact with the UDN Centers to provide guidance on all aspects of metabolomics experimental design, sample collection and storage, sample analysis, and data processing and analysis. We will perform comprehensive, quantitative untargeted and targeted measurements to identify changes in molecular profiles that are associated with rare and undiagnosed diseases, while providing structural determination of novel metabolites associated with undiagnosed diseases. Working closely with the UDN Centers, including the treating physicians, we will integrate metabolomics and genomics data with patient clinical phenotypes to both aid diagnosis and provide mechanistic insight for rare and undiagnosed diseases. This work is significant because it applies state-of-the- art and advanced metabolomics, lipidomics, and glycomics measurements in the study of rare and undiagnosed diseases. This work is innovative because it combines the collective expertise in mass spectrometry and omics measurements of the PNNL team with the expertise in inherited metabolic disease and deep semantic phenotyping of the OHSU team and applies it to the challenge of diagnosis of disease.